Pendred syndrome is the most common form of syndromic deafness and characterized by congenital sensorineural hearing loss and goitre. This disorder was mapped to chromosome 7 and the gene causing Pendred syndrome (PDS) was subsequently identified by positional cloning. PDS encodes a putative transmembrane protein designated pendrin. Pendrin is closely related to a family of sulfate transport proteins that includes the rat sulfate-anion transporter (encoded by Sat-1; 29% amino acid sequence identity), the human diastrophic dysplasia sulfate transporter (encoded by DTD; 32%) and the human sulfate transporter 'downregulated in adenoma' (encoded by DRA; 45%). On the basis of this homology and the presence of a slightly modified sulfate-transporter signature sequence comprising its putative second transmembrane domain, pendrin has been proposed to function as a sulfate transporter. We were unable to detect evidence of sulfate transport following the expression of pendrin in Xenopus laevis oocytes by microinjection of PDS cRNA or in Sf9 cells following infection with PDS-recombinant baculovirus. The rates of transport for iodide and chloride were significantly increased following the expression of pendrin in both cell systems. Our results demonstrate that pendrin functions as a transporter of chloride and iodide, but not sulfate, and may provide insight into thyroid physiology and the pathophysiology of Pendred syndrome.

The Pendred syndrome gene encodes a chloride-iodide transport protein.

I. Introduction II. Developmental Schedules A. Species specificity B. Developmental studies in the rat III. Thyroid Hormone Action A. Sources of T4 and T3 B. The role of maternal thyroid hormone in fetal brain development: direct or indirect? C. Intracerebral transport IV. Molecular Actions of Thyroid Hormone in the Developing Brain A. Nuclear receptors for thyroid hormone in brain B. Thyroid hormone receptor isoforms and their tissue distribution C. Interactions of ligand, receptor, and DNA D. Ontogeny of thyroid hormone receptor isoforms in brain E. Search for T3-responsive genes in the neonatal rat brain F. Regulation of gene expression by T3 through indirect molecular pathways? G. Extranuclear actions of T4? V. Theories and Speculations VI. Conclusions

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Molecular basis of thyroid hormone-dependent brain development.

THE STEROID and thyroid hormones circulate in the plasma tightly bound by albumin and by specific plasma globulins (1, 2). Consequently, hormones exist in two states at equilibrium in vitro, i.e. free (dialyzable) and protein-bound. A widely held hypothesis in endocrinology is that the fraction of hormone that is free in vitro is equivalent to the fraction of hormone that is free and available for transport into tissues in vivo. Therefore, in vitro measurements of free hormones may be commonly used as reliable indices of the free hormone in vivo for a variety of clinical states. The purpose of this review is to advance the concept that the large protein-bound moiety of plasma hormone is available for transport into tissues. Consequently, the fraction of plasma hormone that is available for transport in vivo may deviate greatly from the free fraction in vitro. Under some conditions, changes in the free hormone fraction in vitro and in the fraction of plasma hormone that is available for transport in vivo w...

Transport of protein-bound hormones into tissues in vivo.

The action of thyroid hormones (thyroxine, T4; triiodothyronine, T3) on brain development and function is gaining renewed interest. It has been known for many years that thyroid hormones are very important in mammalian brain maturation, influencing many aspects related to neural cell migration, differentiation, and signaling. In the last 10 years, genes regulated by thyroid hormones have been identified in the rodent brain, and understanding of the role of thyroid hormone nuclear receptors has been facilitated with the analysis of the phenotype of mutant mice for the different receptor isoforms. The general picture that emerges is that T4 and T3 may enter the brain through specific transporters. T4 is converted to the active hormone, T3, in glial cells, astrocytes, and tanycytes, although the main target cells are neurons and maturing oligodendrocytes. T3, acting through the nuclear receptors, controls the expression of genes involved in myelination, cell differentiation, migration, and signaling. In addition to transducing the T3 signal, the nuclear receptors also have activity in the unliganded state (i.e., as aporeceptors), mainly as repressors of transcription. The physiological meaning of aporreceptor action is not known, but they may play a role in the genesis of the hypothyroid phenotype. Among the questions that remain to be explored in more detail is the role of thyroid hormones and the T3 receptors, both liganded and unliganded, in the fetal brain, especially before onset of fetal thyroid gland function. These questions are relevant for human health and the management of thyroid diseases during pregnancy.

Thyroid Hormones and Brain Development

To identify the specific locations of type 2 deiodinase (D2) messenger RNA (mRNA) in the hypothalamus and pituitary gland and determine its regulation by thyroid hormone, we performed in situ hybridization histochemistry, Northern analysis, and quantitative RT-PCR in euthyroid, hypothyroid, and hyperthyroid rats. By in situ hybridization histochemistry, silver grains were concentrated over ependymal cells lining the floor and infralateral walls of the third ventricle extending from the rostral tip of the median eminence (ME) to the infundibular recess, surrounding blood vessels in the arcuate nucleus (ARC), and in the ME adjacent to the portal vessels and overlying the tuberoinfundibular sulci. Silver grains also accumulated over distinct cells in the midportion of the anterior pituitary. In hypothyroid animals, an increase in signal intensity was observed in the caudal hypothalamus, and a marked increase in the number of positive cells occurred in the anterior pituitary. Microdissection of the hypothalam...

Regional distribution of type 2 thyroxine deiodinase messenger ribonucleic acid in rat hypothalamus and pituitary and its regulation by thyroid hormone

Thyroid hormone content of cerebrospinal fluid (CSF) pooled from euthyroid patients was studied because of its possible relationship to brain T4 and T3 levels. The mean CSF total T4 level was 185 ng/100 ml, 1/40 the serum level, and the mean CSF T3 level was 17.4 ng/100 ml, 1/10 the serum level. Mean percent CSF free T4 was 3.5 and free T3 was 10.2. CSF absolute free T4 was 5.8 and absolute free T3 was 1.8 ng/100 ml, both exceeding the respective serum levels of 2.4 and 0.32 ng/100 ml. CSF TBPA bound 12.2% of T3 and 43.5% of T4, higher fractions than serum TBPA which bound 3.0% of T3 and 17.3% of T4. As estimated from maximum T4 binding capacities, the CSF TBG level was 13.2 ng/100 ml, 1/75 of the serum level, and the TBPA level was 1.47 mg/100 ml, 1/12 of the serum level. Although the total levels of T3 and T4 binding proteins were relatively small, thyroid hormone transport in CSF qualitatively resembled that in serum.

Transport of thyroid hormones in serum and cerebrospinal fluid.

THE appearance of permanent hypothyroidism several years after treatment of thyrotoxicosis with radioactive iodine (131I) was pointed out in the review of Chapman and Maloof1 in 1955. Its steadily increasing occurrence during the passage of time was reported in 1961 by Beling and Einhorn.2 The data of Dunn and Chapman3 show that radioactive iodine hypothyroidism occurs in 25 per cent of patients two years after 131I, the rate steadily increasing to 40 per cent after ten years.3 More recently, Nofal, Beierwaltes and Patno4 reported permanent hypothyroidism in 45 per cent after two years, the figure reaching about 70 per . . .

Comparison of high and low dosage levels of 131-I in the treatment of thyrotoxicosis.

RADIOACTIVE iodine therapy effectively controls hyperthyroidism in the majority of patients treated. However, the subsequent appearance of hypothyroidism in some1 has been of increasing concern. Th...

Low-dosage 131-I therapy of thyrotoxicosis (diffuse goiters). A five-year follow-up study.

The spectrum of familial goiter due to iodide organification defect includes goitrous cretins, Pendred's syndrome, and goiter with euthyroidism and normal hearing. One female example of the latter group, now age 16, with goiter since age 6 and 50% perchlorate discharge, underwent thyroidectomy. The thyroid tissue demonstrated lack of peroxidase activity in the tyrosine iodinase, triiodide, guaiacol, and p-hydroxyphenylpyruvic acid (HPPA) assays. An inhibitor,of doubtful significance, was detected in the tissue in both triiodide and guaiacol assays using a soluble bovine thyroid peroxidase as enzyme source. No inhibition was found in the tyrosine iodinase or HPPA assays. Preincubation of the inactive enzymatic preparation from the goiter with hematin restored activity in the tyrosine iodinase assay to normal levels, while activity in the triiodide assay remained negligible. Using other human thyroid peroxidase preparations as controls, it was observed that the reconstructed enzyme from the goiter was more ...

Abnormal thyroid peroxidase causing iodide organification defect.

In a 68-yr-old female with diabetes mellitus and idiopathic cerebral atrophy, therapeutic doses of chlorpropamide or tolbutamide induced a hyponatremic syndrome identical with that of inappropriate secretion of ADH (serum Na 117 mEq/1). Metabolic studies revealed that the hyponatremia was due in part to negative sodium balance. There was no evidence of acute fluid retention since body weight, free water clearance and isotopic extracellular fluid volume were identical during control and drug periods. Diuresis was also absent, indicating inappropriate ADH activity during sulfonylurea-induced hyponatremia. Physicians using sulfonylurea drugs in the management of diabetes mellitus must be alert to the possible complication of hyponatremia.

Garrett A. Hagen

Papers

Transport of thyroid hormones in serum and cerebrospinal fluid.

Comparison of high and low dosage levels of 131-I in the treatment of thyrotoxicosis.

Low-dosage 131-I therapy of thyrotoxicosis (diffuse goiters). A five-year follow-up study.

Abnormal thyroid peroxidase causing iodide organification defect.

Hyponatremia due to sulfonylurea compounds.